Citalopram is a well-known antidepressant drug. It is a selective, centrally acting serotonin (5-hydroxyltryptamine) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat.) 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand.) 1987, 75, 478-486. These publications also disclosed the effects of the compound in the treatment of dementia and cerebrovascular disorders. The structure of citalopram is as follows:

The synthesis of citalopram was first disclosed in U.S. Pat. No. 4,136,193 in 1977 and in DE2657271 in 1979. They both described the preparation of citalopram. As an antidepressant drug, citalopram has been on market in more than sixty countries. There are many patent publications concerning the preparation of citalopram, for example:
1. The starting material 5-cyanophthalide is subjected to: (1) two successive Grignard reactions with 4-bromofluorophenyl and N,N-dimethylaminopropyl chloride, respectively; (2) hydrolysis of the product in dilute acid to obtain citalopram diol intermediate; (3) ring closure with acid; (4) purification and salt formation with bromic acid to obtain citalopram (U.S. Pat. No. 4,560,884).
2. The starting material 5-aminophthalide is subjected to two successive Grignard reactions, hydrolysis, ring closure by dehydration, diazotization and salt formation with bromic acid to obtain citalopram (WO 98/19512).
3. The starting material 5-cyanophthalide is subjected to Grignard reaction with 4-bromofluorophenyl, hydrolysis, reduction by sodium borohydride, ring closure and a second Grignard reaction with N,N-dimethylaminopropyl chloride to obtain citalopram. (WO 9819511).
4. The starting material 5-cyanophthalide is subjected to Grignard reaction with 4-bromofluorophenyl, hydrolysis, esterification, a second Grignard reaction with N,N-dimethylaminopropyl chloride and hydrolysis with acid to obtain citalopram diol intermediate. The intermediate is then subjected to ring closure with acid, purification, and salt formation with bromic acid to obtain citalopram (WO 0012044).
There are many other methods concerning the preparation of citalopram. No matter which is adopted, many purification processes are required in order to obtain relatively purer product. Though many purification processes which may result in the loss of citalopram are employed, the impurities, especially those having similar structures with the product, are hard to eliminate.
It is well known that some of the impurities are from the early starting materials of citalopram or S-citalopram. For example, depending on different starting materials, 5-cyanophthalide can be converted from 5-bromophthalide, 5-chlorophthalide, 5-aminophthalide, 5-amidophthalide, 5-esterphthalide, 5-methylacylphthalide, 5-oxazolinylphthalide, 5-thiazolinylphthalide, 5-carboxylphthalide or phthalide whose 5-substituted group is —O—SO2—(CF2)n—CF3. Due to the incomplete conversion of the early starting materials, those materials as well as the impurities which resulted from the conversion process have similar structures with 5-cyanophthalide, and will more or less exist among 5-cyanophthalide. They will be further converted into other impurities, which have similar structures with citalopram diol intermediate, in the following process of preparing citalopram diol intermediate. The impurities exist among the early starting materials and the intermediates and have similar structures with those materials or intermediates in different stages. They will be further converted into the impurities which have similar structures with the ultimate product during the synthesis process of citalopram or S-citalopram. One or several previously mentioned impurities, other impurities resulted from the conversion and disposal processes may exist among the citalopram diol intermediate. For instance, there may exit impurities like the following III and/or IV.
In Formula III, Z is halogen; —O—SO2—(CF2)n—CF3, wherein n is 0-8; —CHO; —NHR1; —COOR2; —CONR2R3; wherein R2 and R3 is hydrogen, alkyl, any substitutional aryl or arylalkyl, R1 is hydrogen or alkylcarbonyl.
Although there are several disclosed methods such as those in GB2356199, WO03/072565 for purifying citalopram crude product, which can effectively eliminate one or several of the impurities. In GB2356199, a short vacuum distillation is employed, which requires expensive equipments and complex operations. In WO03/072565, complex operations like several salt formation processes and several careful pH adjustments are required. These long purifying processes result in loss of the product while achieving limited results.
It is well-known that citalopram has two enantiomers: S-citalopram and R-citalopram. It is S-citalopram that has the antidepressant activities; R-citalopram hardly has such activities. Presently, S-citalopram salt has been on market. When preparing for S-citalopram, usually chiral organic acid is reacted with the amino group of citalopram diol intermediate. Then the enantiomers are resoluted according to their solubility, or reacted with the 3-substituted hydroxylmethyl of citalopram diol intermediate free base to form diastereomeric esters and then resoluted through crystallization or column chromatography. Among those resolution methods, the most extensively used one is that citalopram diol intermediate is subjected to salt formation with a chiral organic acid and then the obtained enantiomers are resoluted through crystallization. The method is convenient but requires a large amount of chiral organic acid. In addition, WO 03/000672 disclosed a method of resolution non-racemic mixture of S-citalopram and R-citalopram through deposit crystallization. Through separating the deposit and the mother liquor, the enantiomer with a relatively high content was collected in the mother liquor and resoluted. The obtained R-citalopram cannot be used at present. During the stage of resoluting citalopram diol intermediate, the obtained R-citalopram diol intermediate can be effectively used. For instance, WO 03/000672 disclosed a method of converting it into the mixture of R-citalopram and S-citalopram. The mixture was further separated to obtain the racemates of citalopram diol intermediate or mixture of near racemates. It can also be used to form salt with a chiral organic acid and then resoluted or used to prepare citalopram through ring closure.
In GB2357762, citalopram base was purified through crystallization of racemic citalopram free base. The purification of S-citalopram was not yet mentioned, nor was the crystallization of S-citalopram base.
Therefore, a more effective and economical purification method is needed for the industrial production of citalopram. For the preparation of S-citalopram in particular, a more effective and simpler method is needed.